title: Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma.
abstract: BACKGROUND
  Thymic stromal lymphopoietin (TSLP) pathway blockade is a potential strategy for asthma treatment because the main activities of TSLP are activation of myeloid dendritic cells (mDCs) and modulation of cytokine production by mast cells. TSLP-activated mDCs prime the differentiation of naive T cells into inflammatory TH2 cells.
  
  
  OBJECTIVE
  We sought to investigate mechanisms underlying the development of allergic lung inflammation in cynomolgus monkeys using gene expression profiling and to assess the effect of thymic stromal lymphopoietin receptor (TSLPR) blockade in this model.
  
  
  METHODS
  An mAb against human TSLPR was generated and confirmed to be cross-reactive to cynomolgus monkey. Animals were dosed weekly with either vehicle or anti-TSLPR mAb for 6 weeks, and their responses to allergen challenge at baseline, week 2, and week 6 were assessed.
  
  
  RESULTS
  After 6 weeks of treatment, anti-TSLPR mAb-treated animals showed reduced bronchoalveolar lavage (BAL) fluid eosinophil counts, reduced airway resistance in response to allergen challenge, and reduced IL-13 cytokine levels in BAL fluid compared with values seen in vehicle-treated animals. Expression profiling of BAL fluid cells collected before and after challenge showed a group of genes upregulated by allergen challenge that strongly overlapped with 11 genes upregulated in dendritic cells (DCs) when in vitro stimulated by TSLP (TSLP-DC gene signature). The number of genes differentially expressed in response to challenge was reduced in antibody-treated animals after 6 weeks relative to vehicle-treated animals. Expression of the TSLP-DC gene signature was also significantly reduced in antibody-treated animals.
  
  
  CONCLUSIONS
  These results demonstrate promising efficacy for TSLPR blockade in an allergic lung inflammation model in which TSLP activation of mDCs might play a key role.
authors.affiliation: Hoffmann-La Roche, Nutley, NJ 07677, USA.
authors.forename: Donavan T
authors.initials: DT
authors.lastname: Cheng
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ma
authors.forename: Jens
authors.initials: J
authors.lastname: Niewoehner
authors.forename: Martin
authors.initials: M
authors.lastname: Dahl
authors.forename: Angela
authors.initials: A
authors.lastname: Tsai
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Waldemar
authors.initials: W
authors.lastname: Gonsiorek
authors.forename: Subbu
authors.initials: S
authors.lastname: Apparsundaram
authors.forename: Achal
authors.initials: A
authors.lastname: Pashine
authors.forename: Palanikumar
authors.initials: P
authors.lastname: Ravindran
authors.forename: Jimmy
authors.initials: J
authors.lastname: Jung
authors.forename: Julie
authors.initials: J
authors.lastname: Hang
authors.forename: John
authors.initials: J
authors.lastname: Allard
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.forename: Catherine
authors.initials: C
authors.lastname: Tribouley
authors.forename: Satwant
authors.initials: S
authors.lastname: Narula
authors.forename: Stephen
authors.initials: S
authors.lastname: Wilson
authors.forename: Maria E
authors.initials: ME
authors.lastname: Fuentes
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D001249:Asthma / Q000276:immunology / Q000628:therapy*; D006224:Cricetinae; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000628:therapy*; D007249:Inflammation / Q000276:immunology / Q000628:therapy*; D008252:Macaca fascicularis / Q000276:immunology; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors* / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000911:Antibodies, Monoclonal; C498762:CRLF2 protein, human; D016207:Cytokines; D018121:Receptors, Cytokine; D000094632:Thymic Stromal Lymphopoietin
keywords: AHR; Airway hyperresponsiveness; Anti–thymic stromal lymphopoietin receptor antibody; BAL; Bronchoalveolar lavage; DC; Dendritic cell; IC(50); Inhibitory concentration of 50%; Myeloid dendritic cell; T(H)2 inflammation; TSLP; TSLPR; TSLPR mAb; Thymic stromal lymphopoietin; Thymic stromal lymphopoietin receptor; allergen challenge; cynomolgus monkey; dendritic cells; eosinophilia; gene expression profiling; mDC